Device, System and Method for Facilitating Breathing Via Simulation of Limb Movement

ABSTRACT

A device, system and method for increasing air intake by a subject is described. The device includes a vibration motor and a control unit for controlling vibrational motion output by the vibration motor. The methods include positioning the vibration motor on one or more limbs of a subject, and stimulating nerves in the limbs via the generated vibrational motion, whereby the stimulated nerve signals the brain to increase breathing rate or air intake by the subject. Accordingly, the device of the present invention activates nerve fibers that carry kinesthetic cues from the limbs in a pattern that simulates normal limb motion, and thus triggers inherent reflexes that increase ventilation in response to such motion.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application the U.S. national phase application filed under 35U.S.C. §371 claiming benefit to International Patent ApplicationPCT/US14/47642, filed Jul. 22, 2014, which is entitled to priority under35 U.S.0 §119(e) to U.S. Provisional Patent Application No. 61/856,883,filed on Jul. 22, 2013, the contents of which are incorporated byreference herein in its entirety.

BACKGROUND OF THE INVENTION

Multiple respiratory conditions lead to inadequate air intake insubjects to meet their metabolic needs, resulting in an increased levelof carbon dioxide or decreased oxygenation in the body. The conditionsinclude obstruction of the upper airway during sleep, periodic cessationof breathing movements interspersed with breathing efforts, and reducedexcitation of the respiratory musculature from spinal cord injury orimpaired brain processes

Typical interventions to assist breathing in patients with such impairedbreathing patterns include positive pressure ventilation via forced airthrough a face mask or via a tracheostomy, or negative pressureventilation through a sealed chamber, such as an “iron lung.” Positivepressure ventilation through a face mask is unpleasant, remodels theboney facial structure in developing children, and is often rejected bypatients after a short period of use for reasons of discomfort. Atracheostomy poses serious infection concerns. Iron lungs restrictmovement, since the lower body is encased in a chamber, and must becarefully regulated to avoid obstructive sleep apnea.

Other interventions include direct electrical stimulation of the phrenicnerve which serves the diaphragm, a procedure which requires highlyinvasive surgery, together with a potential for phrenic nerve injury. Arisk also exists for a failure of the phrenic stimulating leadspost-surgery, which can potentially have fatal consequences.Experimental procedures are being investigated to assist breathing byelectrical or magnetic stimulation of the spinal cord, but thoseprocedures are not in clinical use.

Thus, there is a need in the art for alternative, non-invasive, devicesand procedures that are easy to use for assisting a subject's breathingor air intake. The present invention satisfies this need.

SUMMARY OF THE INVENTION

A device, system and method for enhancing air intake by a subject aredescribed. The device includes a vibration motor and a control unit forcontrolling vibrational motion output by the vibration motor. Themethods include positioning the vibration motor on at least one limb ofa subject, and stimulating a nerve in the limb via the generatedvibrational motion, whereby the stimulated nerve signals the brain toincrease air intake by the subject. Accordingly, the device of thepresent invention activates proprioceptive nerve fibers that carrykinesthetic cues from the limbs in a pattern that simulates normal limbmotion.

In one embodiment, the at least one limb is the subject's leg. Inanother embodiment, the at least one limb is the subject's arm. Inanother embodiment, the stimulated nerve is the ulnar nerve of the arm.In one embodiment, the at least one vibrator is controlled by a controlunit. In another embodiment, the control unit is programmable. In oneembodiment, the control unit is programmable via a computing device thatis wired or wirelessly connected to the control unit. In anotherembodiment, the control unit controls the vibration motor wirelessly. Inanother embodiment, the device and method may be used while the subjectis sleeping. In one embodiment, the subject has a condition selectedfrom the group consisting of hypoventilation, obstructive sleep apnea,heart failure, central sleep apnea, apnea of prematurity, apnea ofinfancy, muscular dystrophy, spinal cord injury, and stroke.

In one embodiment, the method comprises the delivery of pulses at rateof about 20-70 pulses per minute. In one embodiment, the vibrator isprogrammed to vary inputs such as pulse rate, pulse duration interpulseduration, burst duration, interburst duration, and pulse amplitude. Inanother embodiment, the vibration motor is programmed to pulse in avariable-amplitude sequence. In another embodiment, the vibration motoris between 2-15 mm in diameter. In another embodiment, the vibrationmotor is embedded in a material attached to the subject's limb. Inanother embodiment, the vibration motor is positioned against the skinsurface of the subject's limb and is covered by a material attached tothe subject's limb.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of preferred embodiments of theinvention will be better understood when read in conjunction with theappended drawings. For the purpose of illustrating the invention, thereare shown in the drawings embodiments which are presently preferred. Itshould be understood, however, that the invention is not limited to theprecise arrangements and instrumentalities of the embodiments shown inthe drawings.

FIG. 1 is an image of an exemplary circular vibratory device attached toinsulated wires from a control unit.

FIG. 2, comprising FIGS. 2A-2C, illustrates exemplary positioning of thevibrator over primary sensory fibers from the joints and muscles of asubject's legs, arms or wrists.

FIG. 3 illustrates the positioning of the vibrator on the hand using abandage

FIG. 4, comprising FIGS. 4A and 4B, is an image of an exemplary controlunit of the system.

FIG. 5 is an illustration of the waveform of mechanical vibrationemitted by an exemplary control unit.

FIG. 6 is an image of an exemplary vibrator component attached to thecontrol unit via insulated wires and connector.

FIG. 7 is an image of an exemplary stimulation device that is programmedexternally by a wireless smartphone or tablet through Bluetooth means.The programming characteristics of the pulse sequences are set throughthe external computing device.

FIG. 8 is an image of an exemplary graphical user interface (GUI) of asoftware application on an external computing device which is used toinput and control stimulation parameters to be delivered to the controlunit and vibrator.

FIG. 9 is an image of an exemplary graphical user interface (GUI) of asoftware application on an external computing device which is used toprovide feedback from the control unit and vibrator to the user, and tomonitor the current parameters set in the control unit.

FIG. 10 is an image of an exemplary graphical user interface (GUI) of asoftware application on an external computing device which is used tomonitor and change connection settings of the computing device to thecontrol unit or vibrator.

FIG. 11 is a graph showing the increase in breathing rate accompanyingthree periods of foot movement (indicated by shaded areas) in 30 normalsubjects (control) and 15 children with congenital centralhypoventilation (CCHS), illustrating the effect on breathing withmovement that activates proprioceptor fibers of the foot. It is shownthat even passive movement will elicit the change in breathing, not justsubject-induced movement. It is also shown that the improvement inbreathing rate is enhanced in the CCHS group with disturbed breathingduring sleep.

FIG. 12, comprising FIG. 12A-Figure 12C, depicts the results of anexperiment examining the effect of limb stimulation on the respirationof subjects. The respiratory analysis of two subjects (FIG. 12A and FIG.12B) demonstrate that stimulation facilitates the breathing in eachsubject. FIG. 12C demonstrates that stimulation reduces respiratorydisturbance index (RDI) in each subject.

FIG. 13, comprising FIG. 13A and FIG. 13B, depicts the results of anexperiment examining the effect of limb stimulation on the integrity ofsleep stages from two different subjects, where stimulation was inducedon night two of each subject. In FIG. 13A, the sustained periods ofwaking when the subject should be sleeping was reduced in Night 2. InFIG. 13B, stimulation induced much longer periods of rapid eye movementsleep (REM sleep) in the second night with stimulation.

FIG. 14, comprising FIG. 14A through FIG. 14C, depicts the results of anexperiment examining the effect of stimulation of the hand on a patientwith congenital central hypoventilation. FIG. 14A: Respiratory tracings(airflow) from Pre (Baseline), Stimulation on hand, and Post Stimulationperiods from a 2 year old congenital central hypoventilation patientunder clinical intervention. FIG. 14B: Peak-to-trough amplitude ofairflow, and index of air exchange, in Pre (Baseline), Stimulation ofhand, and Post Stimulation periods in arbitrary units. FIG. 14C:Respiratory rate in Baseline, Stimulation, and Post Stimulation periods.Stimulation significantly enhanced amplitude, without changing therespiratory rate.

FIG. 15 illustrates the breathing patterns of a subject with obstructivesleep apnea with (Stim On) and without (Apnea, No Device) limbstimulation. The data demonstrates that, without the device, there is aseries of obstructive events that reduces airflow and oxygen saturation.However, during stimulation, the breathing pattern of the subject ismuch improved.

DETAILED DESCRIPTION

It is to be understood that the figures and descriptions of the presentinvention have been simplified to illustrate elements that are relevantfor a clear understanding of the present invention, while eliminating,for the purpose of clarity, many other elements found in typicalassisted breathing devices and techniques. Those of ordinary skill inthe art may recognize that other elements and/or steps are desirableand/or required in implementing the present invention. However, becausesuch elements and steps are well known in the art, and because they donot facilitate a better understanding of the present invention, adiscussion of such elements and steps is not provided herein. Thedisclosure herein is directed to all such variations and modificationsto such elements and methods known to those skilled in the art.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described.

As used herein, each of the following terms has the meaning associatedwith it in this section.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

“About” as used herein when referring to a measurable value such as anamount, a temporal duration, and the like, is meant to encompassvariations of ±20%, ±10%, ±5%, ±1%, and ±0.1% from the specified value,as such variations are appropriate.

Throughout this disclosure, various aspects of the invention can bepresented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity, andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, 6 and any wholeand partial increments therebetween. This applies regardless of thebreadth of the range.

The present invention is based in part on the discovery that vibrationalstimulation of proprioceptor fibers of the limb of a subject enhancesbreathing. The coupling of breathing with limb motion reaches back toobservations made of breathing patterns in race horses on cold days whensynchronization of expired breath with leg movements could be noted, andhas since been documented in a large number of physiological studies inboth animals and humans (Eldridge et al., 1985, Respir Physiol, 59:313-337; Fink et al, 1995, J Physiol, 489(Pt 3): 663-675; Iscoe andPolosa,1976, J Appl Physiol, 40: 138-148; Potts et al., 2005, JNeurosci, 25: 1965-1978). Effects of limb motion are independent fromcarbon dioxide drive (Pan et al., 1986, J Appl Physiol, 60: 1016-1024),an extremely important aspect in cases where, through genetic or otherinjury, brain structures which mediate carbon dioxide drive are damaged,and that drive is missing. This aspect is a special concern in cases ofcongenital hypoventilation syndrome, where such patients areunresponsive to carbon dioxide and fail to breathe during sleep. Evenquiescent behavior, such as watching television, often results inhypoventilation and life-threatening falls in oxygenation in thesepatients.

However, it has been observed that such children may increaseventilation with active exercise, such as when playing soccer (Paton etal., 1993, The Am Rev Respir Dis 147: 1185-1191). Cyclic movement of thefeet in affected children increases breathing (Gozal et al., 1996, Am JRespir Crit Car Med, 153: 761-768), and that relationship is maintainedeven during sleep (Gozal and Simakajornboon, 2000, Am J Respir Crit CarMed, 162: 1747-1751). The means by which that coupling between limbmovement and breathing occurs has been explored with functional magneticresonance imaging, and demonstrates the integration of the limb andrespiratory musculature systems (Harper et al., 2005, Society forNeuroscience Abstracts, 352.1). Unfortunately, provoking such limbmovement during sleep, or even during waking hours, is oftenimpractical.

Thus, the present invention includes a system and device to simulatesignals from the limbs that are interpreted by the brain as movement,and through coupling of those signals with activity inrespiratory-related brain areas, elicit enhanced breathing efforts orrate by the subject. Since walking or running is not feasible duringsleep or other daily activities, the present invention can be used toactivate a subject's brain areas governing breathing that use the neuralactivity normally generated with such limb movement.

In certain embodiments, the present invention facilitates breathing in asubject suffering from hypoventilation via stimulation of a region of atleast one of the subject's limbs. For example, in certain aspects theinvention provides stimulation of proprioceptive afferent fibers locatedfor example at the back of the knee, palm of the hand, back of theelbow, wrist, and the like. For example, the invention may stimulatefibers in one or more toes, feet, ankles, legs, fingers, arms, wrists,or hands. Stimulation will increase breathing rate in both normalsubjects and subjects with hypoventilation, but is much more effectivein subjects with hypoventilation.

The device of the present invention activates nerve fibers that carrykinesthetic cues from the limbs in a pattern that simulates normal limbmotion. As contemplated herein, the device includes a mechanicalvibrator and a programmable control unit that controls the vibrator. Thepresent invention is unique in that stimulation of the subject isunrelated to carbon dioxide stimulation, positive pressure ventilation,and electrical stimulation of the respiratory system. Unlike theseexisting techniques, the present invention instead incorporatesnon-invasive neural processes to provide increases in ventilation toimprove oxygen delivery to tissue.

The device of the present invention uses a vibratory device to activatethe same sensory nerves as those carrying signals indicating footmovement, thus signaling the brain to increase respiratory rate withoutrequiring increased carbon dioxide stimulation normally needed toincrease breathing rate.

For example, as shown in FIG. 1, the mechanical vibrator may be a small,circular vibrator with a diameter of approximately 7 mm. Preferably, thevibration motor is between about 2-15 mm in size to localize thevibration stimulus to the underlying nerve fibers. However, it should beappreciated that the vibration motor may be of any type, size ordimension as understood by those skilled in the art, provided thevibrator is capable of neural stimulation, as described herein.

As contemplated herein, the vibrational stimulator may be placed on atleast one region of the subject's limb. In some embodiments, a singlevibrator is positioned on a limb for neural stimulation, and in otherembodiments, multiple vibrators are positioned on one or more limbs forneural stimulation. For example, one or more vibrators may be positionedon one or more toes, feet, ankles, legs, fingers, arms, wrists, or handsof a subject being treated. The vibrator may be placed on the surfaceskin overlying sensory nerves which normally carry signals on limbmotion, to stimulate the nerves through mechanical vibration at rateswhich mimic patterns of activity found during limb activity accompanyingmovement. In one embodiment, the vibrator is placed directly onto thesubject's skin surface, for example on the surface of the skin of theankle overlying the tibial nerve. In another embodiment, at least onelayer of fabric, polymer or other material is placed between thesubject's skin surface and the vibrator. In another embodiment, thevibrator is embedded in a material, such as a fabric or an elasticmaterial such as neoprene or other polymer. For example, as shown inFIG. 2, the vibrator may be placed over primary sensory fibers from thejoints and muscles of the subject's feet, legs, arms or hands, andsecured into position via an elastic bandage or a wrapping, such as aVelcro wrap, to maintain position. As shown in FIG. 2A, a Velcro bandmay include an embedded vibrator overlying a sensory nerve carryingkinesthetic sensation from the foot and ankle to simulate movementduring walking. Vibrators can also be placed above the knee to stimulatenerves carrying sensory information from that joint. As shown in FIG.2B, the vibrator can be placed over sensory nerves within the wrist, oras shown in FIG. 2C, the vibrator can be placed over the ulnar nerve ofthe arm near the elbow to stimulate nerves simulating arm movement. Suchupper limb placements may be favorable for subjects with spinal cordinjury, where sensory nerve information from the lower limbs may belost; these patients often require assistance in breathing, especiallyduring sleep, since innervation to abdominal respiratory muscles isoften diminished. In certain embodiments, the vibrator is placed on thehand or palm of a subject (FIG. 3). For example, as depicted in FIG. 3A,the vibrator may be secured to an adhesive bandage. The bandage can thenbe applied to a suitable position on the hand or palm of the subject(FIG. 3B and FIG. 3C). Optionally, the present invention may furtherinclude a device to open a subject's airway to facilitate breathing.Non-limiting examples of such devices include mouthpieces or oralappliances commonly used for treatment of snoring or sleep apnea.

As shown in FIG. 4, the vibrator is controlled by a programmable controlunit to induce vibrations. For example, the vibrator may beswitch-programmed to pulse in a variable-amplitude sequence that evokesnerve fiber discharge similar to that arising from walking or running.As contemplated herein, the control unit may be programmed to vary thepulse rate, pulse interval, duration of pulses, duration of pulse-burstinterval, and pulse amplitude (to increase or decrease force of thevibrator) as desired, such that the delivered vibrational energy iscapable of neural stimulation, as described herein.

The pulse rates are established to mimic signals from moving limbsmatching a rate of movement found to be effective in increasingrespiratory rate in normal children and children with congenital centralhypoventilation syndrome (Macey et al., 2005, Society for NeuroscienceAbstracts 635.13). However, the rates may change with age, sincemimicking extension and flexion of the leg will change as the rate ofwalking slows with age.

For example, in certain embodiments, the device is programmed to deliverone or more set of pulses, via the vibrator, to the subject. Forexample, in one embodiment, the device delivers a continuous train ofpulses for a defined period.

In one embodiment, the pulses are delivered at rate of about 1-200pulses per minute. In one embodiment, the pulses are delivered at rateof about 10-100 pulses per minute. In one embodiment, the pulses aredelivered at rate of about 20-70 pulses per minute. In one embodiment,the pulses are delivered at rate of about 62 pulses per minute.

In one embodiment, each pulse is delivered at about 10-1000 Hz. In oneembodiment, each pulse is delivered at about 100-500 Hz. In oneembodiment, each pulse is delivered at about 152 Hz.

In one embodiment, the duration of each individual pulse, (i.e., pulseduration) is about 0.01-60 seconds. In one embodiment, the pulseduration is about 0.1-10 seconds. In one embodiment, the pulse durationis about 0.2-1 seconds. In one embodiment, the pulse duration is about0.4 seconds.

In one embodiment, the duration between successive pulses (i.e.,inter-pulse duration) is about 0.01-60 seconds. In one embodiment, theinter-pulse duration is about 0.1-10 seconds. In one embodiment, theinter-pulse duration is about 0.2-1 seconds. In one embodiment, theinter-pulse duration is about 0.4 seconds.

In one embodiment, the total time period where the pulses are delivered,including pulse duration and interpulse duration, is about 1 second-1000minutes. In one embodiment, the total time period where the pulses aredelivered is about 1-500 minutes. In one embodiment, the total timeperiod where the pulses are delivered is about 5-100 minutes.

In certain embodiments, the device delivers one or more sets or burstsof pulses, where each burst comprises one or more pulses and where eachburst is separated by an inter-burst interval. For example, in oneembodiment, the device delivers a plurality of bursts, where each burstcomprises a pulse train, and where each burst is separated by aninter-burst interval.

In one embodiment, the duration of each burst is about 1 second-1000minutes. In one embodiment, the duration of each burst is about 1-500minutes. In one embodiment, the duration of each burst is about 5-100minutes.

In one embodiment, the duration of the inter-burst interval is about 1second-1000 minutes. In one embodiment, the duration of the inter-burstinterval is about 1-500 minutes. In one embodiment, duration of theinter-burst interval is about 5-100 minutes.

In certain embodiments, the entire stimulation protocol, including forexample a continuous train of pulses or a plurality of bursts of pulses,is repeated as suitable over minutes, hours, days, and the like.

The parameters of the stimulation, including for example, pulseduration, burst duration, interpulse interval, interburst interval, andmay vary substantially to meet the needs for activating upper airwaymuscles over those of the diaphragm, or for particular breathingconditions where more rapid or slower respiratory efforts are desired.Specific stimulation paradigms for various conditions are describedelsewhere herein.

The amplitude of the pulses from the vibration unit can be set by theprogramming device, and can be set to maximal displacement to accountfor individuals with excessive fat or tissue over the nerve fibers, orto lower levels in cases where very little tissue separates the surfaceof the skin from the nerve fibers. Pulse amplitudes may be set lower toavoid arousals during sleep states where excessive vibration may lead tounnecessary wakenings. In certain embodiments, the device may provide arange of amplitudes in the range of about 0-2 G (vibrational force),where G is gravitational acceleration, and equals 9.8 m/s². In certainembodiments, the device is controlled by the user to control theparticular amount of vibrational force needed or desired.

In one embodiment, the programmable control unit is battery powered. Forexample, in one embodiment, the control unit comprises a 9V battery. Incertain embodiments, the battery is rechargeable. For example, incertain aspects the battery may be wirelessly recharged using componentsand techniques known in the art. In one embodiment, the programmablecontrol unit comprises an isolated plug for accessing electricity from ahome, hospital or other location providing access to an electrical powersource. In one embodiment, the control unit is electrically connected tothe vibrator via an electrical lead, cable or wire, as shown in FIG. 6.For example, the device may comprise one or more leads carrying low DCvoltage to the vibrator. In one embodiment, the control unit comprisesmultiple outputs for communication with multiple individual vibrators.For example, the control unit may communicate with two or more differentvibrators, delivering the same or different stimulation parameters tothe two or more vibrators. In other embodiments, the vibrator includes awireless receiver and a power source so that the vibrator component mayreceive signals from the control unit wirelessly. In one embodiment, thecontrol unit comprises a memory device to store different stimulationprotocols, user data, and the like.

In one embodiment, the control unit may include a user interfaceincluding a display screen to provide text or other graphics indicatinguser information, such as stimulation parameters of amplitude, duration,intervals, battery power level, and the like. The user interface mayalso include one or more depressible buttons, dials, recessed switchesor a touch screen through which the control unit may be programmed by auser.

In one embodiment, the programmable control unit or vibrator receivesstimulation parameters via a computing device, such as a computer,laptop, smartphone, tablet, watch, television, or the like (FIG. 7). Forexample, the device of the invention may be controlled directly by awireless computing device, such as tablets, smartphones or otherwireless digital/cellular devices that are Bluetooth or network enabled,and includes a software application platform or portal providing a userinterface as contemplated herein. The computing devices may include atleast one processor, standard input and output devices, as well as allhardware and software typically found on computing devices for storingdata and running programs, and for sending and receiving data over anetwork. In certain embodiments, the computing device comprises adisplay suitable for visual representation of system control and status.The communications between the computing device and the control unit orvibrator may be conducted via any wireless based technology, including,but not limited to radio signals, near field communication systems,hypersonic signal, infrared systems, cellular signals, GSM, and thelike.

In certain embodiments, the computing device comprises a softwareapplication used for the input of stimulation parameters, delivery ofstimulation parameters, storage of stimulation protocols, storage ofuser information, and the like. The software application platform may bea local or remotely executable software platform, or a hosted internetor network program or portal.

The software platform includes a graphical user interface (GUI) forinputting stimulation parameters, modulating function of the controlunit and vibrator, and for displaying information regarding thehistorical or real-time functionality of the device, as well ashistorical or real-time functionality of the subject's respiratoryactivity. In certain embodiments, wireless communication for informationtransfer to and from the computing device may be via a wide area networkand may form part of any suitable networked system understood by thosehaving ordinary skill in the art for communication of data to additionalcomputing devices, such as, for example, an open, wide area network(e.g., the internet), an electronic network, an optical network, awireless network, personal area networks such as Bluetooth, a physicallysecure network or virtual private network, and any combinations thereof.Such an expanded network may also include any intermediate nodes, suchas gateways, routers, bridges, internet service provider networks,public-switched telephone networks, proxy servers, firewalls, and thelike, such that the network may be suitable for the transmission ofinformation items and other data throughout the system.

As would be understood by those skilled in the art, the computing devicemay be wirelessly connected to the expanded network through, forexample, a wireless modem, wireless router, wireless bridge, and thelike. Additionally, the software platform of the system may utilize anyconventional operating platform or combination of platforms (Windows,Mac OS, Unix, Linux, Android, etc.) and may utilize any conventionalnetworking and communications software as would be understood by thoseskilled in the art.

To protect data, an encryption standard may be used to protect filesfrom unauthorized interception over the network. Any encryption standardor authentication method as may be understood by those having ordinaryskill in the art may be used at any point in the system of the presentinvention. For example, encryption may be accomplished by encrypting anoutput file by using a Secure Socket Layer (SSL) with dual keyencryption. Additionally, the system may limit data manipulation, orinformation access. Access or use restrictions may be implemented forusers at any level. Such restrictions may include, for example, theassignment of user names and passwords that allow the use of the presentinvention, or the selection of one or more data types that thesubservient user is allowed to view or manipulate.

In certain embodiments the network provides for telemetric data transferto and from the control unit, vibrator, and computing device. Forexample, data transfer can be made via any wireless communicationtechnology, including, but not limited to radio signals, near fieldcommunication systems, hypersonic signal, infrared systems, cellularsignals, GSM, and the like. In some embodiments, data transfer isconducted without the use of a specific network. Rather, in certainembodiments, data are directly transferred to and from the control unitand computing device via systems described above.

The software may include a software framework or architecture thatoptimizes ease of use of at least one existing software platform, andthat may also extend the capabilities of at least one existing softwareplatform. The software provides applications accessible to one or moreusers (e.g. patient, clinician, etc.) to perform one or more functions.Such applications may be available at the same location as the user, orat a location remote from the user. Each application may provide agraphical user interface (GUI) for ease of interaction by the user withinformation resident in the system. Exemplary GUIs of the invention areprovided in FIG. 8-FIG. 10, which depict the ability for a user tocontrol and monitor the stimulation parameters of the device. A GUI maybe specific to a user, set of users, or type of user, or may be the samefor all users or a selected subset of users. The system software mayalso provide a master GUI set that allows a user to select or interactwith GUIs of one or more other applications, or that allows a user tosimultaneously access a variety of information otherwise availablethrough any portion of the system. Presentation of data through thesoftware may be in any sort and number of selectable formats. Forexample, a multi-layer format may be used, wherein additionalinformation is available by viewing successively lower layers ofpresented information. Such layers may be made available by the use ofdrop down menus, tabbed pseudo manila folder files, or other layeringtechniques understood by those skilled in the art.

The software may also include standard reporting mechanisms, such asgenerating a printable results report, or an electronic results reportthat can be transmitted to any communicatively connected computingdevice, such as a generated email message or file attachment. Likewise,particular results of the aforementioned system can trigger an alertsignal, such as the generation of an alert email, text or phone call, toalert a patient, doctor, nurse, emergency medical technicians, or otherhealth care provider of the particular results.

Exemplary GUIs of the system of the present invention are depicted inFIG. 8-FIG. 10. For example, in one embodiment, the software comprises acontrol layer, status layer, a settings layer, and menu layer. In oneembodiment, each layer is accessible by a user to allow for controland/or observation of data relating to the selected layer. Uponselection by a user, each layer provides a unique GUI that allows forinteraction with the layer. Layers may be selected using tabs, drop downmenus, and other strategies known in the art. For example, in certainembodiments, the computing device and software allow for touch-sensitiveinteraction, where the GUIs of the system are interacted with via touchof the display. In certain embodiments, the GUIs of the system areinteracted with using standard computing hardware, including, but notlimited to, a keyboard, mouse, and the like.

In one embodiment, the software of the system comprises a control layerand a control GUI. The control GUI comprises tools to control pulsecharacteristics (FIG. 8). For example, the GUI comprises text fields,drop down menus, sliders, buttons, and the like which allow a user toinput stimulation parameters, as described elsewhere herein. The controlGUI allows for input of, for example, pulse duration, interpulseduration, pulse amplitude, and the like, for multiple connectedvibrators, thereby allowing for independent control of each vibratorbeing implemented. In certain embodiments, the control GUI allows forinput of the baseline duration (time between start of procedure andonset of vibration), task period (duration of vibration period includinginter-pulse intervals), the idle period (the idle time betweensuccessive vibration or task periods), and the number of repeats (thetotal number of repeated vibration or task periods). In certainembodiments, the control GUI allows for input of the amplitude levels ofvibration of each vibrator. For example, an entire period may include abaseline period of 30 sec before vibration starts, a 300 sec taskperiod, 30 sec idle time between the next 300 sec period, with each 300sec period being repeated 5 times, thereby providing five stimulationperiods of 5 minutes per period. In one embodiment, the control GUIprovides an option for sending the inputted parameters to the controlunit. Further, the control GUI provides a Start/Stop button to initiatestimulation based upon the inputted parameters. The control GUI may alsoallow for directly turning the vibrators on or off, either for testingor for treatment purposes. In certain embodiments, the control GUIallows the user to save one or more parameters which can then be loadedfor future use.

In one embodiment, the software of the system comprises a status layerand a status GUI. The status GUI is designed to provide feedback fromthe control unit and/or vibrator to the user, and to monitor the currentparameters set in the control unit (FIG. 9). For example, the status GUImay comprise fields that indicate the pulse width, interpulse time,baseline duration, task period, idle period, and number of repeats setin the control unit. Further, in certain embodiments the status GUIdisplays the set vibration power level for each vibrator, where “powerlevel” indicates the vibrational amplitude, expressed in percentage ofmaximum possible amplitude. In certain embodiments, the status GUIcomprises one or more fields indicating the elapsed time, timeremaining, and total time of a stimulation protocol. In one embodiment,the status GUI comprises a field displaying the number of faultsdetected and/or registered by the control unit. In one embodiment, thestatus GUI comprises a button for clearing of the fault memory. Incertain embodiments, the status GUI comprises one or more indicators ofthe on/off state of each vibrator and the battery state of the controlunit. In one embodiment, the status GUI comprises a refresh toggle orswitch that allows the user to select whether the parameters of thestatus GUI auto refreshes at a defined refresh interval (e.g., everyhalf second). In one embodiment, the status GUI displays a graph toindicate the overall stimulation protocol as well as the currentposition, in time, of the stimulation process.

In one embodiment, the software of the system comprises a settings layerand a settings GUI. The settings GUI allows the user to monitor andchange connection settings of the computing device to the control unitand/or vibrator (FIG. 10). For example, the settings GUI providesoptions for controlling the Bluetooth or wireless settings of thesystem. In one embodiment, the settings GUI comprises a switch thatallows the user to enable and disable communication to and from thecomputing device. For example, the switch may turn off the Bluetooth orwireless communication of the computing device. In one embodiment, thesettings GUI comprises a switch to establish a connection (e.g., aBluetooth connection or wireless connection) to the control unit and/orvibrator of the system. For example, if the communication of thecomputing device is enabled, a user can then establish communication tothe control unit and/or vibrator. In certain embodiments, the settingsGUI comprises a list of available devices which may be selected in orderto establish connection. In one embodiment, connection to a device ismade by manually entering the name, MAC address, or other identifyingfeature of the device. In one embodiment, the settings GUI comprises arefresh button to allow the user to refresh a list of recently-paired ornearby devices. In one embodiment, the settings GUI comprises a powersaving switch that allows the user to enable the power saving mode ofthe system. For example, a power saving mode disconnects the controlunit and vibrator from the computing device and renders the control unitand/or vibrator in a power saving state while remained in a poweredstate. The settings GUI may comprise a display traffic switch thatenables display of all incoming and outgoing data. In certainembodiments, the settings GUI comprises one or more fields for sending amessage or command to the connected device.

In one embodiment, the software of the system comprises a menu layer anda menu GUI. In one embodiment, the menu GUI allows a user to save thecurrently set stimulation parameters in the control unit or in thecomputing device. In one embodiment, the menu GUI comprises an optionfor exiting the software.

The present invention provides a method for facilitating breathing in asubject in need thereof. For example, the method may stimulate breathingto enhance sleep-disordered breathing. However, the method may also beused to assist compromised breathing in wakefulness.

Sleep-disordered breathing can generally be categorized into severalbreathing patterns, each of those patterns associated with differentdiseases. These patterns are now briefly described.

Hypoventilation

The term “hypoventilation” is a general phrase, referring to a broadrange of inadequate ventilation from a number of potential sources. Onesource is that from neuromuscular diseases, such as Muscular Dystrophy,characterized by widespread muscle weakness, resulting in obstructivesleep apnea or insufficient muscle action to ensure adequate gasexchange. Spinal cord injury below cervical levels can result inimpaired motoneuron outflow to thoracic and abdominal respiratorymusculature, reducing ventilation. Enhanced airway resistance, or UpperAirway Resistance Syndrome results from a range of processes thatresemble obstructive sleep apnea. The condition typically can only bedetected with esophageal balloons or specialized sound devices, andleads to impaired ventilation and a range of cardiovascularconsequences. The present invention can assist in all of theseconditions, by further exciting upper airway muscles in patients withincreased airway resistance, by recruiting more effort from weakenedmuscles of muscular dystrophy cases, and by providing additional neuraldrive to thoracic and abdominal musculature in spinal cord patients.

In one embodiment, the present invention may be used to facilitatebreathing in a subject diagnosed with hypoventilation or respiratorydepression. In certain embodiments, the present invention may be used tofacilitate breathing in a subject having polio, congenital centralhypoventilation syndrome (CCHS), muscular dystrophy, chronic obstructivepulmonary disease, spinal cord injury, injury to brain stem and highcervical spinal cord areas, genetic conditions which damage structuresmediating sensitivity of brain areas to carbon dioxide drives tobreathing, or even heart failure. Assistance for spinal cord andmuscular dystrophy cases may be especially necessary during sleep, butventilation during wakefulness is also a concern. In another embodiment,the present invention may be used to facilitate breathing in an infantsuffering from apnea of prematurity. Such apnea typically consists ofperiodic breathing, i.e., patterns of no respiratory action (silence)interspersed with respiratory movements. Vibration intervention willfacilitate action of respiratory muscles during those silent periods. Instill other embodiments, the present invention may be used to facilitatebreathing in a subject desiring more consistent or enhanced air intakefor recovering muscles, such for use by an athlete resting after arigorous workout. Examples of enhancing ventilation in spinal cordpatients are shown in FIG. 12A-FIG. 12C, and the resulting improvementin sleep state integrity in FIG. 13A and FIG. 13B. Examples of enhancingventilation in a child with congenital central hypoventilation is shownin FIG. 14.

Obstructive Sleep Apnea (OSA)

OSA is characterized by the collapse of the upper airway from inactionof upper airway respiratory muscles (e.g., genioglossal fibers of thetongue) with continued diaphragmatic efforts. The condition arises fromloss of central neural coordination of drive to the upper airway musclesfrom phrenic nerve discharge to the diaphragm and spinal nerveactivation of the thoracic wall/abdominal musculature. The blockade ofthe airway is now often treated by use of devices such as oralappliances commonly used for treatment of snoring or sleep apnea, orforcing air through an oral or nasal mask to dilate the upper airway,normally accomplished by continuous positive airway pressure (CPAP)devices, or devices to force air triggered to the inspiratory cycle ofbreathing.

The condition is defined as a separate entity, but accompanies a rangeof other conditions which exacerbate, and perhaps contribute to theinitial development of OSA. These conditions include obesity, nasalobstruction by septal deviation sinusitis, nasal polyps chronicrhinitis, stenosis, or issues which contribute reduction of oral size,including enlarged tonsils/adenoids, hypothyroidism, and micrognathia.Strokes (especially cerebellar strokes), and menopause development(reduction in respiratory drive hormones, alterations in cervical columnand oral airway) can also contribute. OSA also frequently accompaniesDown's syndrome, Sickle Cell Anemia, heart failure, Alzheimer's Disease,epilepsy, and Cystic Fibrosis.

The system and method of the present invention can assist breathing inOSA by recruiting upper airway muscles in a timely fashion to dilate theupper airway by activating upper airway musculature just prior todiaphragmatic descent. That is, the invention promotes the opening theairway so that negative pressure from the diaphragm will not collapsethe soft upper airway tissue. For example, it has been demonstrated fromfunctional magnetic resonance imaging studies, that activation of theproprioceptors by passive foot movement activates portions of the braininvolved in exciting upper airway musculature as well as thediaphragmatic musculature (Harper et al., 2005, Society for NeuroscienceAbstracts 352.1; Macey et al., 2005, Society for Neuroscience Abstracts635.13). These studies provide evidence that the present invention wouldbe useful in facilitate breathing in a subject with OSA. In preliminarystudies, the device has reduced the incidence of apnea in an OSA subjectby a factor of four. Further, as shown in FIG. 15, limb stimulation of asubject with OSA enhances the breathing patterns of the subject. It isshown that, without the device, there is a series of obstructive eventsthat reduces airflow and oxygen saturation. However, during stimulation,the breathing pattern of the subject is much improved.

Central Apnea

Central apnea is a failure of the brain to provide sufficient “drive” toactivate any of the respiratory musculature, resulting in inadequateintake of oxygen and exhalation of carbon dioxide. Central apnea canresult from congenital disorders, such as mutation of PHOX2b, resultingin congenital central hypoventilation syndrome, or brain injuryresulting from strokes, trauma, hemorrhage, or drug action, damage ofthe cervical spinal cord at levels C3, C4, or C5, and also appears inapnea of infancy, although such apnea is often periodic (describedbelow). The present invention may be used to facilitate breathing in asubject with central apnea, as numerous studies have demonstratedimproved ventilation with passive limb movement in congenital centralhypoventilation, clinical use in recovery from apnea by passive footstimulation in neonates, and improved breathing with rocking of infants.

Periodic and Cheyne-Stokes Breathing

Periodic breathing, found in apnea of infancy, drug action, andbreathing at altitude, and Cheyne-Stokes breathing, a more severe formof periodic breathing, which occurs in conditions such as heart failure,and is a significant characteristic of the latter condition, result froma loss of coordination of ventilation-significant incoming signals ofCO₂ and O₂ from the periphery (due to altered perfusion and otheraspects), and central drive to breathing, arising from descendingthermal and other forebrain drives and central chemoreceptors. Thepattern is characterized by a succession of breaths, typically arisingin a crescendo pattern, and then declining, followed by a loss of allrespiratory effort, and repeated with another succession of breaths. Thefailure is one of coordination loss, which can be assisted by overridingthe chemoreceptor signals from the significant proprioceptive drive ofthe device and method of the invention.

One example of a stimulation pattern that has been demonstrated toimprove breathing during sleep in spinal cord patients was a continuoustrain of pulse durations of 0.4 sec, inter-pulse duration of 0.4 sec,task time 460 min, idle time 0, repeats 1. Another example of astimulation pattern for obstructive sleep apnea comprised of bursts oftrains with pulse durations of 0.1 sec, inter-pulse time 0.1 sec, burstduration of 2 sec, interburst duration of 2 sec, task time, 230 min,repeats 1. The specific stimulation pattern will vary with subject ageand condition.

Subjects with congenital central hypoventilation syndrome benefit morefrom a pattern of vibration over proprioceptor fibers that simulate theburst-pause pattern of proprioceptor nerves responding to extending andflexing the limb during walking. Thus, a pulse duration of 1.0 sec,interpulse duration of 1.0 sec, with a task duration of 460 min,adequate for an all-night recording, would simulate the nerve pattern ofdischarge accompanying normal walking of an adult; the pulse durationand interpulse duration would be correspondingly shorter in a child, orif increased ventilation corresponding to running would be desired. Theamplitude of vibration would normally be fixed at levels sufficient tostimulate the nerves underling the skin. However those levels may vary,depending on the skin thickness in adults over children or infants.

EXPERIMENTAL EXAMPLES

The invention is further described in detail by reference to thefollowing experimental examples. These examples are provided forpurposes of illustration only, and are not intended to be limitingunless otherwise specified. Thus, the invention should in no way beconstrued as being limited to the following examples, but rather, shouldbe construed to encompass any and all variations which become evident asa result of the teaching provided herein.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the present invention andpractice the claimed methods. The following working examples therefore,specifically point out the preferred embodiments of the presentinvention, and are not to be construed as limiting in any way theremainder of the disclosure.

Example 1 Limb stimulation in subjects with congenital centralhypoventilation (CCHS)

Experiments were conducted to examine the effect of limb stimulation onthe breathing rate of subjects with congenital central hypoventilation(CCHS). FIG. 11 shows the increase in breathing rate accompanying threeperiods of foot movement (indicated by shaded areas) in 30 normalsubjects (control) and 15 children diagnosed with congenital centralhypoventilation syndrome. Foot movement substantially increasedbreathing rate, and much more so in the patients than in normalsubjects.

The purpose of this experiment was to demonstrate the basic tenet of thepresent method, that nerve signals from foot movement enhance breathing,and is particularly effective in particular patients with breathingdisorders. Respiratory movements were recorded by an air-filled bag heldin place with a belt on the thoracic wall; a non-compliant tube leadfrom the bag to a pressure transducer. All physiologic signals wererecorded on a laptop data acquisition system (InstruNet; GW Instruments,Somerville Mass., USA). The respiratory signal was sampled at 100 Hz.Passive foot motion was induced by investigator-initiated manualextension/flexion at 23 flexions/min. The leg was raised at the calf sothat the movement occurred at the ankle, with flexion and extension ofthe foot being maximal and consistent. The rate of 23 flexions/min waschosen as sufficiently rapid to facilitate breathing, while still beingcomfortable for the subject. Movements were performed by a researcherwho maintained foot contact for the entire period to minimize novelsensory responses. The same procedure was then repeated for the oppositefoot; initial selection of left or right foot was random. Respiratoryand heart rates were derived from the peak-to-peak intervals in recordedsignals. Breathing rates were calculated from the thoracic movementsignal. The mean rates were calculated for all subjects across the threeperiods of passive foot movements, and displayed with inter-subjectstandard errors across the entire period. The data show that respiratoryrates increased during periods of foot movements in control subjects,and increased more for congenital central hypoventilation subjects.Those data provide evidence that nerve signals from foot movement canenhance breathing rates.

An experiment was conducted examining the effect of vibrationalstimulation of the hand on the respiration of a subject with CCHS.Respiratory tracings (airflow) from Pre (Baseline), Stimulation on hand,and Post Stimulation periods from a 2 year old congenital centralhypoventilation patient under clinical intervention is shown in FIG.14A. It was observed that stimulation significantly enhanced amplitude,without changing the respiratory rate (FIG. 14B and FIG. 14C).

Example 2 Respiratory analysis of subjects before and after stimulation

Experiments were conducted to examine the effects of limb stimulation onthe respiration of breathing-impaired subjects. The subjects were twoyoung adult patients with severe spinal injury at upper thoracic levelsat least 1 year post-trauma. Subjects were instrumented with thoracicwall and abdominal excursion sensors, oxygen saturation sensors,electroencephalographic, eye movement, and electrocardiograph leads (3lead ECG) (SomnoMedics Inc; Fla.) for recording of physiologicalmeasures and assessment of sleep state, and recorded for two consecutivenights. Vibration devices were placed on the palms of the left hand, andparameters were set at continuous vibration with pulse durations of 0.4sec, inter-pulse duration of 0.4 sec, and continued for 460 min. FIG.12A and FIG. 12B show numerical values for respiratory measures fromsubject 1 and subject 2, respectively. FIG. 12C demonstrates that therespiratory disturbance index (RDI) decreased for the two studiedsubjects during stimulation. For example, subject 1 had an RDI of 67.4on night 1 (before stimulation) and 18.2 on night 2 (duringstimulation). Subject 2 had an RDI of 23.3 on night 1 (beforestimulation) and 6.3 on night 2 (during stimulation).

Example 3 Sleep stages

Experiments were conducted to examine the effects of limb stimulation onthe sleep stages of subjects. FIG. 13A and FIG. 13B depict the sleepstages of a two subjects on nights 1 and 2. These studies were carriedout concurrently with the respiratory measures on the same spinal cordpatients described above in Example 2, i.e., thoracic-level spinalinjury young adults, with the same vibrator placement and stimulationparameters and length of recording. The thoracic and abdominal measuresof breathing, electrocardiographic, oxygen saturation andelectroencephalographic signals were collected by a Somnomedicsacquisition system, and analyzed by Somnomedics software to determinesleep states. Minute-by-minute determination of sleep states werecalculated and displayed (FIG. 13A and FIG. 13B). It is demonstratedthat the sustained periods of waking when the subject should be sleepingwas reduced in Night 2 (FIG. 13A). Further, stimulation induced muchlonger periods of rapid eye movement sleep (REM sleep) in the secondnight with stimulation (FIG. 13B). The disclosures of each and everypatent, patent application, and publication cited herein are herebyincorporated herein by reference in their entirety.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

1. A method for increasing air intake by a subject, comprising:positioning at least one vibrator on at least one limb of a subject; andstimulating a nerve in the at least one limb via vibrational motiondelivered by the at least one vibrator, whereby the stimulated nerveinteracts with the subject's brain to increase air intake by thesubject.
 2. The method of claim 1, wherein the at least one limb is thesubject's leg.
 3. The method of claim 1, wherein the at least one limbis the subject's arm.
 4. The method of claim 3, wherein the stimulatednerve is the ulnar nerve.
 5. The method of claim 1, wherein the at leastone vibrator is controlled by a control unit.
 6. The method of claim 5,wherein the control unit is programmable.
 7. The method of claim 6,wherein the control unit is programmable via a computing device wired orwirelessly connected to the control unit.
 8. The method of claim 5,wherein the control unit controls the at least one vibrator wirelessly.9. The method of claim 1, wherein the subject is sleeping.
 10. Themethod of claim 1, wherein stimulating the nerve comprises delivery ofpulses via the at least one vibrator, where the pulses are delivered ata rate of about 20-70 pulses per minute.
 11. The method of claim 10,wherein the delivery of pulses is repeated.
 12. The method of claim 1,wherein the subject has a condition selected from the group consistingof hypoventilation, obstructive sleep apnea, heart failure, centralsleep apnea, apnea of prematurity, apnea of infancy, muscular dystrophy,spinal cord injury, and stroke.
 13. A method of treating hypoventilationin a subject, comprising stimulating a nerve in at least one limb of thesubject via vibrational motion, wherein the stimulated nerve elicits abrain response which enhances breathing effort by the subject.
 14. Asystem for enhancing the breathing of a subject, comprising: at leastone vibration motor; a control unit communicatively connected to the atleast one vibration motor; and a means for securing the at least onevibration motor to at least one limb of a subject; wherein the controlunit initiates a signal to the at least one vibration motor to generatevibrational motion to the at least one limb of the subject, such thatthe vibrational motion stimulates a nerve in the at least one limb toelicit an enhanced breathing effort by the subject.
 15. The system ofclaim 14, wherein the control unit is programmable.
 16. The system ofclaim 14, wherein the control unit controls the vibration motorwirelessly.
 17. The system of claim 15, wherein the at least onevibration motor is programmed to vary inputs from the group selectedfrom the pulse rate, pulse duration, interpulse duration, burstduration, interburst duration, and pulse amplitude.
 18. The system ofclaim 15, wherein the at least one vibration motor is programmed topulse in a variable-amplitude sequence.
 19. The system of claim 14,wherein the at least one vibration motor is between 2-15 mm in diameter.20. The system of claim 14, wherein the means for securing the at leastone vibration motor to at least one limb of a subject comprisesembedding the at least one vibration motor in a material attached to thesubject's limb.
 21. The system of claim 14, wherein the means forsecuring the at least one vibration motor to at least one limb of asubject comprises positioning the vibration motor against the skinsurface of the subject's limb and covering the vibration motor with amaterial attached to the subject's limb.